People with diabetes are more likely to have cardiovascular disease (CVD) and kidney disease. The majority of the excess risk of CVD in diabetes is restricted to patients with diabetes and diabetic kidney disease (DKD). New data indicates that apolipoprotein C3 (APOC3) plays a critical role in diabetic atherosclerosis and preliminary data suggests that it is causally linked to DKD. APOC3 is a key regulator of triglyceride-rich lipoprotein (TLR) metabolism. It is in turn regulated by insulin, but also by kidney disease. Our overall hypothesis is that diabetes and kidney disease raise APOC3 levels. Increased levels of TRLs and their remnants, driven by APOC3, accelerate diabetic kidney disease as well as atherosclerosis. This hypothesis will be tested in 2 separate aims: Aim 1: Does blocking APOC3 prevent diabetic kidney disease? This will be tested in 2 different mouse models of diabetes and kidney disease using 2 different approaches to target APOC3; a specific antisense (ASO) to APCO3 and a transcription factor (CREBH) that has profound effects selectively on TLR-associated APOC3. Aim 2: Does renal impairment and diabetes act synergistically to elevate APOC3, contributing atherosclerosis? To test the hypothesis that diabetes and reduced renal function act synergistically to elevate plasma APOC3 to accelerate atherosclerosis we will induce renal impairment in non-diabetic and diabetic mice using 5/6 nephrectomy. APOC3 levels will be reduced in these mice using both APOC3 ASO treatment and hepatic overexpression of CREBH to test the causal role of APOC3. The majority of the excessive CVD risk in diabetes is present in patients who also have DKD. With the diabetic population growing, finding new therapeutic targets is exceedingly important. We propose a novel common mechanism whereby DKD and CVD are accelerated by APOC3-mediated increases in TRLs and their remnants, and a new way that both can be prevented by blocking APOC3. These studies are likely to reveal important similarities in the mechanisms whereby APOC3 promotes two of the major complications of diabetes. A human APOC3 ASO has already been tested in T2DM patients with promising TRL-lowering results, thus APOC3 might be a therapeutic target for combating the rising epidemic of diabetic complications.